Is PRF1 p.Arg410Pro (c.1229G>C) pathogenic?

PRF1 p.Arg410Pro (c.1229G>C) is classified Pathogenic/Likely pathogenic in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: ambiguous (0.4087); Very rare (popmax 0.00254%, nfe); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Arg410Pro (c.1229G>C)?

PRF1 p.Arg410Pro (c.1229G>C) is associated with familial hemophagocytic lymphohistiocytosis 2, hereditary hemophagocytic lymphohistiocytosis, aplastic anemia (ClinVar).

How common is PRF1 p.Arg410Pro (c.1229G>C) in the general population?

PRF1 p.Arg410Pro (c.1229G>C) is very rare (popmax 0.00254%, nfe) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRF1 p.Arg410Pro (c.1229G>C)?

AlphaMissense predicts ambiguous (score 0.4087) — an in-silico prediction, not a clinical call.

PRF1 p.Arg410Pro

c.1229G>C · rs150558419 · VCV2136869

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
AlphaMissense	0.4087	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -9.27	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.2, phastCons 0.41
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,998 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,613,394 alleles · very rare exomes 30/1,461,282 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,333
African / African-American	0.00134%	74,900

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PRF1
Protein: p.Arg410Pro
Coding: c.1229G>C
MANE Select: NM_001083116
dbSNP: rs150558419
Type: single nucleotide variant
Location: chr10:70598492 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 410: the c2 domain

Full PRF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hemophagocytic lymphohistiocytosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemophagocytic lymphohistiocytosis aplastic anemia

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

PRF1 p.Arg410Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
PRF1 p.Arg410Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PRF1 p.Arg410= Likely benign ★ same residue
PRF1 c.539+2T>A Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg225Trp Pathogenic ★★ ⚠ same condition
PRF1 p.Arg232Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg299Cys Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg356Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/prf1-p-arg410pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown